Precision Medicine in Myelodysplastic Syndromes and Leukemias: Lessons from Sequential Mutations

Abstract

Precision medicine can be simply defined as the identification of personalized treatment that matches patient-specific clinical and genomic characteristics. Since the completion of the Human Genome Project in 2003, significant advances have been made in our understanding of the genetic makeup of diseases, especially cancers. The identification of somatic mutations that can drive cancer has led to the development of therapies that specifically target the abnormal proteins derived from these mutations. This has led to a paradigm shift in our treatment methodology. Although some success has been achieved in targeting some genetic abnormalities, several challenges and limitations exist when applying precision-medicine concepts in leukemia and myelodysplastic syndromes. We review the current understanding of genomics in myelodysplastic syndromes (MDS) and leukemias and the limitations of precision-medicine concepts in MDS.

Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents

“…First line standard therapeutic approaches in elderly highrisk (HR) MDS or AML patients are largely based on hypomethylating agents (HMAs) including azacitidine (AZA) or decitabine (DAC), but responses are generally short-lived and occur only in 50-60% of patients [1,2]. Patients failing HMAs have a dismal prognosis with a median survival of around 5 months [3].…”

Introductory Chapter: Progress in Myelodysplastic Syndrome Area

“…Myelodysplastic syndromes (MDS) constitute a group of age-associated heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis with peripheral cytopenias, dysplasia, and an increased risk of progression to acute myeloid leukemia (AML) [1][2][3][4][5][6]. About 50% of cases of MDS are characterized by the presence of cytogenetic abnormalities.…”

“…However, one or more driver mutations in most patients with MDS are associated with the pathogenesis of MDS. Gene mutations affect proteins involved in various important cell processes as RNA-splicing, DNA methylation, histone and chromatin modifications, signal transduction, transcription (transcription factors), tumor suppressor (TP53), RAS pathway, and separation of sister chromatids during cell division (cohesion complex) [4,[8][9][10].…”

Treatment options for lower-risk myelodysplastic syndromes. Where are we now?

“…Patients with intermediate-risk disease scored by IPSS-R are further stratified into higher or lower risk groups based on the presence of high-risk somatic mutations, an IPSS-R score of >3.5, the presence of circulating myeloblasts, or transfusion dependency. 7–10…”

“…Patients with intermediate-risk disease scored by IPSS-R are further stratified into higher or lower risk groups based on the presence of high-risk somatic mutations, an IPSS-R score of >3.5, the presence of circulating myeloblasts, or transfusion dependency. [7][8][9][10] In addition to the prognostic scoring system, morphology of the disease based on World Health Organization 2016 criteria can herald behavior. Patients with MDS-ring sideroblasts (RS)-singlelineage dysplasia/MDS-RS are considered to have better prognosis, especially those harboring the SF3B1 somatic mutation.…”